Abstract 2510: Pentraxin-3 associated up-regulation of genes involved in motility, angiogenesis, and inflammation in glioblastoma
Authors: Umadevi V. Wesley, Ian Sutton, Dylan E. Nelson, Paul A. Clark, Robert J. Dempsey
Journal: Cancer Research (2023)

Abstract Glioblastoma, a malignant brain cancer, is highly invasive and resistant to multimodal treatment partly due to distorted vasculature and exacerbated inflammation in its tumor microenvironment. The glycoprotein pentraxin-3 (PTX3), a modulator of inflammation, is correlated with the severity of some cancers. However, the mechanism responsible for the oncogenic role of PTX3 in GBM malignancy remains unclear. Our previous study examined the role of PTX3 in GBM growth, angiogenesis, and invasion using in vitro glioblastoma cells and in vivo/pre-clinical GBM models, proteomic profiling, molecular and biochemical approaches. Over-expression of PTX3 in U87 brain tumor cells correlated with cell cycle progression, increased migratory potential, and survival under hypoxic conditions. PTX3 over-expression increased blood vessel forming ability of endothelial cells. Importantly, PTX3 over-expression increased tumor growth, micro-vessel density, and invasion in brains of an orthotopic mouse model. To understand the molecular mechanisms associated with PTX3 mediated tumor aggressiveness, we further examined the effects of PTX3 on mRNA levels of genes involved in motility/invasion, angiogenesis, and inflammation using pathway specific gene arrays. PTX3 over expression was associated with the 5-fold upregulation of hypoxia-inducible factor (HIF)-1α, which in turn transactivates several genes essential for tumor growth and survival. Indeed, higher PTX3 expression led to increased mRNA levels of genes involved in motility, angiogenesis, and inflammation. The upregulated motility associated genes included ARHGEF7, RAC1, and PAK, a protein kinase involved in intracellular signaling pathways downstream of integrins. Inflammatory genes that were increased in expression included IL-1beta, CCL3, CCL5, and CXCL5 that amplifies a proinflammatory cytokine response via a phosphatidylinositol 3-kinase-NF-kappa B pathway. The upregulated pro-angiogenic genes included interleukin-8 (IL-8), matrix metalloproteinase-2 (MMP2), and vascular endothelial growth factor (VEGF), expression of which correlates with GBM malignancy. Interestingly PTX3 decreased the levels of thrombospondin-1 that inhibits angiogenesis. Thus, PTX3 appears to trigger multiple signaling pathways that enhance the aggressive behavior of tumor cells. Taken together, our study indicates that targeted therapy such as blocking PTX3 may reduce the aggressiveness of glioblastomas through regulation of multiple molecular pathways. Citation Format: Umadevi V. Wesley, Ian Sutton, Dylan E. Nelson, Paul A. Clark, Robert J. Dempsey. Pentraxin-3 associated up-regulation of genes involved in motility, angiogenesis, and inflammation in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2510.